PROJECT SUMMARY/ABSTRACT Mitochondrial deficits is one of the early and prominent features of Alzheimer?s disease and a large body of studies suggest mitochondrial dysfunction could trigger the pathogenesis of AD. However, the underlying mechanism remains elusive. Recent progress in mitochondrial studies highlight the unique mitochondrial structural system and its implication under both physiological and pathological conditions. In particular, it is well known that mitochondrial inner membrane connects outer membrane by the individual contact site, which forms neck-like tubule to communicate inter-membrane space and intra-cristae space. A growing body of studies unveiled the molecular machinery in maintaining the integrity of mitochondria by the mitochondrial contact site and cristae organizing system (MICOS). It is not surprising that impaired MICOS greatly deteriorates mitochondrial morphology and function. Importantly, abnormal MICOS is associated with several human diseases including nervous diseases, which underscores the significance of analyzing the MICOS in the most prevalent neurodegenerative disease in the world. In this regard, we investigated the integrity of MICOS in human brains of AD and control cases. Our preliminary data suggest there were changes of MICOS related mitochondrial cristae structure in the cortical neurons of human AD brains by electron microscopy analysis. In addition, there were deficits in proteins levels, neuronal distributions of core MICSOS components and assembly of MICOS complex in human AD brains in the pilot study. Altogether, both structural and biochemical analysis suggested the impaired MICOS in AD brain. These exciting discoveries raised a critical question of whether and how impaired neuronal MICOS contributed to the mitochondrial dysfunction and neuronal loss in the AD. In this application, as the first step to characterize the potential role of abnormal MICOS changes in mitochondrial dysfunction and pathogenesis of AD, we will explore the changes of MICOS and its consequences and correlation with other mitochondrial/neuronal deficits in AD models both in vitro and in vivo. As the first study to specifically determine the potential involvement of MICOS abnormalities in causing mitochondrial dysfunction and pathogenesis of AD, our proposal will likely pave the road for larger studies to shed new light on a novel mechanism underlying mitochondrial dysfunction in the pathogenesis of AD and provide innovative therapeutic targets for future drug development to fight against AD.